Macrophages are primary immune cells involved in obesity-triggered chronic low-grade inflammation in adipose tissues. Prostaglandin (PG) E2, mainly generated from macrophages, can regulate adipose tissue remodeling. Here, we observed that PGE2 receptor subtype 3 (EP3) was remarkably downregulated in adipose tissue macrophages from high-fat diet (HFD)-fed mice and patients with obesity. Notably, macrophage-specific deletion of EP3 exacerbated HFD-induced obesity in mice, whereas EP3α isoform overexpression in macrophages alleviated obesity phenotype in HFD-fed mice. EP3 deficiency suppressed anti-adipogenic secreted protein acidic and rich in cysteine (SPARC) secretion in macrophages. SPARC deletion in macrophages abrogated the protection of EP3α-overexpression against HFD-induced obesity in mice. Mechanistically, EP3 activation promoted SPARC expression by suppressing DNA methylation in macrophages through the PKA/Sp1/Dnmt1/3a signaling cascade. EP3 agonist treatment ameliorates HFD-induced obesity in mice. Thus, EP3 inhibits adipogenesis through promoting macrophage releasing SPARC and may serve as a therapeutic target for managing diet-induced obesity.